1. Field of the Invention
The process of the present invention produces an antibacterial agent of the class commonly called semi-synthetic penicillins and, preferably, of the subclass characterized by an .alpha.-amino group on the acyl sidechain at the 6-position as in ampicillin and amoxicillin.
2. Description of the Prior Art
The first commercial penicillin having an .alpha.-amino group on the 6-acylamido sidechain was ampicillin, which is 6-(D-.alpha.-amino-.alpha.-phenylacetamido)penicillanic acid (see U.S. Pat. No. 2,985,648).
Amoxicillin is an antibacterial agent used in human therapy and marketed as the trihydrate of the free acid (i.e., the zwitterion). It is described, for example, in J. Chem. Soc. (London), pages 1920-1922 (1971) and Antimicrobial Agents and Chemotherapy--1970, pages 407-430 (1971) and in U.S. Pat. No. 3,674,776 (see also U.S. Pat. No. 3,192,198). Its chemical name is 6-[D-.alpha.-amino-.alpha.-(p-hydroxyphenyl)acetamido]penicillanic acid.
The use of amino acid chloride hydrochlorides to make such penicillins was disclosed in the patent literature, e.g. in U.K. Pat. No. 938,321 and U.K. Pat. No. 959,853 under anhydrous conditions (the latter utilized the protection during acylation of the carboxyl group of the 6-aminopenicillanic acid with a silyl group as was also disclosed in U.K. Pat. No. 1,008,468 and U.S. Pat. No. 3,249,622) and in U.K. Pat. No. 962,719 in cold aqueous acetone. These penicillins are amphoteric amino acids and use was therefore made in their isolation (e.g. as disclosed in U.S. Pat. No. 3,157,640 and U.S. Pat. No. 3,271,389) of certain aliphatic unsymmetrical branched chain secondary amines (often called liquid amine resins) which had previously been used in the isolation of 6-aminopenicillanic acid which is also an amphoteric amino acid (see U.S. Pat. No. 3,008,956). Improved methods of isolating and purifying such penicillins were disclosed, e.g. in U.S. Pat. No. 3,180,862 via .beta.-naphthalene sulfonates and in U.S. Pat. No. 3,198,804 via intermediate isolation and subsequent facile hydrolysis of hetacillin.
The use of a silyl group to protect the carboxyl group of a natural penicillin during chemical cleavage to 6-aminopenicillanic acid was disclosed in U.S. Pat. No. 3,499,909. The use of silylated 6-aminopenicillanic acid during anhydrous acylation with amino acid chloride hydrochlorides was disclosed in numerous patents, e.g. U.S. Pat. No. 3,478,018; U.S. Pat. No. 3,595,855; U.S. Pat. No. 3,654,266; U.S. Pat. No. 3,479,338 and U.S. Pat. No. 3,487,073. Some of these patents also disclose use of liquid amine resins. See also U.S. Pat. Nos. 3,912,719, 3,980,637 and 4,128,547.
U.K. Pat. No. 1,339,605 contains various specific and detailed examples for preparing amoxicillin by the reaction of a silylated derivative of 6-aminopenicillanic acid with a reactive derivative (including the chloride hydrochloride) of D-(-)-.alpha.-amino-p-hydroxyphenylacetic acid in which the amino group is protected, thereafter removing the silyl group(s) by hydrolysis or alcoholysis and thereafter, when possible, recovering the amoxicillin, usually as the crystalline trihydrate. Thus crystalline amoxicillin was obtained in Example 1 by isoelectric precipitation from an aqueous solution, e.g. at pH 4.7. Purification was presumably achieved by this example by dissolving the crude product (before isoelectric precipitation) in water at an acidic pH such as 1.0 (e.g. in aqueous hydrochloric acid) in the presence of a water-immiscible organic solvent such as methyl isobutyl ketone (4-methylpentan-2-one). Much the same procedure was used in U.S. Pat. No. 3,674,776.
A search of Chemical Abstracts Formula Indexes Vols. 58-87 showed that I had not been indexed. ##STR1##
Siloxycarbonylamino derivatives are indexed under silanol, carbamic acid and under N-carboxy derivatives of compounds as the trimethylsilyl ester.
However, the following papers appear of some interest:
1. Breederveld, H.: The interaction of dialkylaminosilanes with carbon disulphide. A novel reaction in organosilicon chemistry. Recueil, 79, 1126 (1960).
2. Cragg, R. H.; Lappert, M. F.: Amino-derivatives of metals and metalloids. Part IV. Aminosilylation and aminophosphination of some unsaturated substrates. J. Chem. Soc. (A), 82-85 (1966).
3. Kricheldorf, H. R.: Herstellung von N-Silyloxycarbonylaminosaure-derivaten. Synthesis, 259-60 (1960) (Ger.); C. A. 73, 45820r (1970).
4. Kricheldorf, H. R.: The preparation of amino acid N-carboxyanhydrides (NCAs) from N-siloxycarbonyl amino acid trimethylsilyl esters. Chem. Ber., 104, 87-91 (1971) (Ger.); C. A. 74, 54156b (1971).
5. Mironov, V. F.; Kozyukov, V. P.; Kirilin, A. D., et al.: Synthesis and reactions of silyl carbamates. New method for the preparation of organic isocyanates without the use of phosgene. Zh Obshch Khim, 45, 1971-73, (1975).
6. Sheludyakov, V. D.; Kirilin, A. D.; Mironov, V. F.: New method for the preparation of (carbamoyloxy)silanes. Zh Obshch Khim, 45, 471 (1975).
7. Mironov, V. F.; Sheludyakov, V. D.; Kirilin, A. D.: Siloxycarbonylation of amines. Zh Obshch Khim, 46, 2297-98 (1976).
8. Farbenfabriken Bayer A-G (Oertel, G., et al.): Organosilicon compounds. Chem. Abs., 60, 6868b. (Ger. Offen. No. 1,157,226).